title: Novel heterocyclic-fused pyrimidine derivatives: synthesis, molecular modeling and pharmacological screening.
abstract: Novel heterocyclic-fused pyrimidines viz pyrrolo[1,2-c]pyrimidines 4-8, pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 9-14, pyrimido[4',5':4,5]pyrimido[1,6-a]azepines 16-18, pyrrolo[1',2':1,6]pyrimido[4,5-d][1,3]thiazines 19a,b and 1,3-thiazino[4',5':4,5]pyrimido[1,6-a]-azepine 19c were designed and synthesized as potential anticancer agents. In this investigation all the newly synthesized compounds were subjected to cytotoxic screening against MCF-7 breast cancer cell line. Moreover, kinase inhibitory assay was done for compounds 5, 7, 9 and 18 against the non-receptor and receptor tyrosine kinases c-Src and VEGFR, respectively. The tested compounds were more potent against c-Src than VEGFR, and the highest activity was observed for 18 showing 81% c-Src activity inhibition. Finally, molecular docking was performed with c-Src and VEGFR in an attempt to simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. Electronic address: rkarafa@cu.edu.eg.
authors.forename: Reem K
authors.initials: RK
authors.lastname: Arafa
authors.forename: Mai S
authors.initials: MS
authors.lastname: Nour
authors.forename: Nehad A
authors.initials: NA
authors.lastname: El-Sayed
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D040262:Receptors, Vascular Endothelial Growth Factor; D019061:src-Family Kinases
keywords: Antiproliferative agents; Fused pyrimidines; MCF-7 breast cancer cell line; c-Src and VEGFR inhibition